Compounds bearing sulphamoyl and amidino radicals, their preparation process and pharmaceutical compositions containing them

ABSTRACT

The subject of the invention is the compounds of formula I ##STR1## in which Ar 1  represents naphtyl, phenyl, quinolyl or isoquinolyl optionally substituted; 
     Ar 2  represents a phenyl or thienyl optionally substituted; 
     R 1 , R 2  and R&#39; 2  are independently of each other, H or (C 1  -C 4 )alkyl; 
     R 1  represents nothing and N is attached to Ar 2 , and optionally R 2  and R&#39; 2  form a double bond; or R 1  or R 2  is attached to Ar 2  and represents a (C 1  -C 3 )alkylene; 
     R 3  and R 4 , which are identical or different, represent H, (C 1  -C 4 )alkyl or form, with the nitrogen atom to which they are attached, a (C 5  -C 7 ) saturated heterocycle selected from pyrrolidine, piperidine and hexahydroazepine; 
     Z 1  represents a (C 1  -C 12 )alkylene, optionally interrupted or extended by a (C 5  -C 7 )cycloalkyl or phenyl; 
     Q 1  represents methyl, amino, alkoxycarbonylamino, alkylamino, dialkylamino, a (C 5  -C 7 ) saturated heterocyclic amino group, amidino, alkylamidino, guanidino, alkylguanidino, pyridyl, imidazolyl, pyrimidinyl, indolyl, hydroxy, alkoxy, (C 2  -C 8 )alkoxycarbonyl, amino(C 1  -C 4 )alkyl-N-(C 1  -C 4 )alkylamino or carbamoyl, or phenyl optionally substituted; 
     Q 2  represents H or alkyl; 
     Q 3  represents H or (C 1  -C 4 )alkyl; 
     or Q 1  and Q 3  are attached to form a heterocycle and together represent a (C 2 ) or (C 3 )alkylene, whereas Z 1  represents nothing, in the form of pure enantiomers or mixtures thereof in any proportions, as well as their salts with acids. 
     These compounds have an affinity for the biological receptors of neuropeptides Y (NPY), which are present in the central and peripheral nervous system.

The present invention relates to new compounds containing,simultaneously, especially a substituted sulphamoyl and an amidinogroup, to the process for preparing them and to pharmaceuticalcompositions containing them.

These compounds have in particular a certain affinity for the biologicalreceptors of neuropeptide Y, NPY, which are present in the central andperipheral nervous systems.

Neuropeptide Y was identified only about ten years ago, and very fewagonists or antagonists are currently known for its receptors which arenot polypeptides, whose use in therapy is not easy, especially becauseof their degradation in the gastrointestinal tract; a recent review inDrugs of the Future 17 (1) 39-45 (1992) mentions benextramine, aninositol phosphate and an antihistamine derived fromguanidinoalkylimidazole.

Compounds with a structure similar to that of the compounds of theinvention have been described in EP-A-0,236,163 and EP-A-0,236,164; theycorrespond to the formula A; ##STR2## in which R'₁, R'₂, R'₃ and R'₄ areespecially alkyls or phenyls. These compounds are anticoagulants andanti thrombotic agents, such that this document could not suggest theactivity of the present compounds.

The compounds of the invention correspond to the formula I: ##STR3## inwhich Ar₁ represents naphtyl, phenyl, quinolyl or isoquinolyl optionallysubstituted by Cl, F, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy hydroxy or (C₁-C₄)dialkylamino;

Ar₂ represents a phenyl or thienyl optionally substituted by Cl, F, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy or hydroxy;

R₁, R₂ and R'₂ are independently of each other, H or (C₁ -C₄)alkyl;

R₁ represents nothing and N is attached to Ar₂, and optionally R₂ andR'₂ form a double bond;

or R₁ or R₂ is attached to Ar₂ and represents a (C₁ -C₃)alkylene;

R₃ and R₄, which are identical or different, represent H, (C₁ -C₄)alkylor form, with the nitrogen atom to which they are attached, a (C₅ -C₇)saturated heterocycle selected from pyrrolidine, piperidine andhexahydroazepine;

Z₁ represents a (C₁ -C₁₂)alkylene, optionally interrupted or extended bya (C₅ -C₇)cycloalkyl or phenyl;

Q₁ represents methyl, amino, alkoxycarbonylamino, alkylamino,dialkylamino, a (C₅ -C₇) saturated heterocyclic amino group, amidino,alkylamidino, guanidino, alkylguanidino, pyridyl, imidazolyl,pyrimidinyl, indolyl, hydroxy, alkoxy, (C₂ -C₈)alkoxycarbonyl, amino(C₁-C₄)alkyl-N-(C₁ -C₄)alkylamino or carbamoyl, phenyl or phenylsubstituted by Cl, F, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy or hydroxy;

Q₂ represents H or alkyl;

Q₃ represents H or (C₁ -C₄)alkyl;

or Q₁ and Q₃ are attached to form a heterocycle and together represent a(C₂) or (C₃)alkylene, whereas Z₁ represents nothing, and the additionsalts of these compounds with acids.

The linear or branched alkyl and alkoxy groups correspond to (C₁ -C₄)unless otherwise indicated; the saturated heterocyclic amino groups maybe pyrrolidinyl, piperidino, morpholino, piperazinyl or4-alkylpiperazinyl. The phenyls, unless otherwise indicated, may besubstituted by Cl, F, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy or hydroxy.

The salts are generally prepared with pharmaceutically acceptable acidsbut the salts of other acids which are useful for the purification orisolation of the products of formula I also form part of the invention.

The compounds of formula I comprise in general two asymmetric carbonsand the 4 pure enantiomers as well as mixtures thereof, in anyproportions, are within the invention.

The compounds according to the invention can be prepared from thecompounds of formula II: ##STR4## by processes whose principles areknown, which a person skilled in the art will be able to adapt to thereactivity and solubility of the products used.

Many processes for the synthesis of amidines are described in the book"The chemistry of amidines and imidates" D. G. Neilson Ed Saul Patai;Wiley & Sons--p. 389-394 (1975). In general, the nitrile is converted toan imidate salt by reacting an alcohol in a strong acid medium, in aso-called Pinner reaction, and this imidoester, optionally in free form,is reacted with the amine of formula III: ##STR5## in a non-reactivepolar solvent, preferably in an alcohol, at a temperature of between 0°C. and the reflux temperature of the solvent.

Most of these amines (III) are known and the new products can beprepared by applying principles and methods well known to a personskilled in the art. For example, for the derivatives in which Q₁ is animidazolyl, reference can be made to U.S. Pat. No. 3,881,016 and toSynth. Communic. 17, 223-227 (1987) or when Q₁ is at-butoxycarbonylamino group, to Synth. Communic. 20 (16), 2559-2564(1990).

The compounds of formula I in which Q₁ represents NH₂ or alkylamino canbe prepared by hydrolysis of the compounds of formula I in which Q₁ is at-butoxycarbonylamino group.

The compounds of formula I in which Q₁ represents a substituted orunsubstituted guanidino group can be prepared, by reacting with thecompound in which Q₁ =NH₂, a compound of formula ##STR6## in which Rrepresents H or alkyl and Z represents a nucleofuge, such as SO₃ H, forexample under the conditions described in Tetrahedron Letters 3183-3186(1988) with aninoiminomethanesulphonic acids theN-methylaminoiminomethanesulphonic acid can be obtained as described inJ. Org. them. 51 1882 (1986).

The compounds of formula I in which the amidine group is included in aheterocycle can be prepared in a manner known per se by reacting adiamine H₂ N--(CH₂)_(n) --NH₂ in which n is 2 or 3, with the imidoester,optionally by reacting a diamine in which one of the groups is protectedby a labile group which will be removed before cyclization.

A certain number of processes for the preparation of the nitriles offormula II in which Ar₁ is naphthyl, R₁ =R₂ =R'₂ =H are described inEP-A-0,236,163 and reference can be made thereto, especially forpreparing the pure enantiomers from each pure stereoisomer of4-cyanophenylalanine in which the carboxylic acid group will be blocked,optionally, in the form of an amide substituted by R₃ and R₄ as informula I; this compound will be reacted with the alpha-amino acid offormula IV: ##STR7## in which the amino group will be protectedbeforehand either in the form of sulphamoyl Ar₁ --SO₂ --N< as in formulaI, or by a labile group such as t-butoxycarbonyl, which will be removedafter the coupling, in a conventional manner, by reaction of a stronganhydrous acid.

Processes for the preparation of amides by reaction of a carboxylicgroup and an amino group, which are carried by 2 asymmetric carbons,without racemization around any one of these carbons, can also be foundin numerous publications relating to the chemistry of peptides andespecially in: The Peptides. Ed. E. Cross and J. Meienhofer vol. 1,65-104 (1979)--Acad. Press.

In general, these reactions occur at temperatures of between 0° and 40°C., in an inert solvent such as dichloromethane, acetonitrile,tetrohydrofuran or dimethylformamide, in the presence of at least oneequivalent of a tertiary amine such as triethylamine or preferably inthe presence of N-ethylmorpholine.

The sulphamoyl group Ar₁ --SO₂ --N--R₁ can be obtained in a conventionalmanner, by reacting a sulphochloride Ar₁ --SO₂ --Cl in the presence of abase, optionally in a two-phase medium, in the presence of a phasetransfer catalyst, either with the amino acid IV or a correspondingalkyl ester, or with the nitrile of formula V: ##STR8##

When R₁ is different from H, the nitriles II can be obtained by reactingR₁ X with the sulphonamide II in which R₁ is H, in the presence of abase, X representing a halogen atom or a sulphonate group.

The alpha-amino acids of formula IV or the corresponding aliphaticesters are known compounds or can be prepared by processes similar tothose used for the known derivatives. Reference is especially made toGreenstein and M. Winitz in "Chemistry of the amino acids", J. Wiley andSons Inc. ed., (1961) p. 697-714 and p. 2693-2770, and G. C. Barrett in"Chemistry and Biochemistry of the amino acids", Chapman and Hall ltd.ed., 1985, p. 246-353. For example, when R'₂ =H, by means of a Schiffbase as described in Synthesis 313-315 (1984), according to the reactionscheme: ##STR9## in which R"₁ and R"₂, represent phenyl rings, R"₃represents alkyl and Ar₂ has the same meaning as in formula I.

The amino acids of formula IV in which R₂ is different from H may beobtained via a similar route. In this case, the Schiff base issuccessively alkylated by Ar₂ CH₂ X and R₂ X in tetrahydrofuran in thepresence of a base such as an alkali metal alkoxide at -70° C.-+25° C.

In order to obtain the amino acids of formula IV, or the correspondingesters in the form of one of the pure enantiomers, fractionalrecrystallizations of a salt of the racemate can be carried out with anoptically active acid or base, according to a technique whose principleis well known; one of the enantiomers of a racemic ester of an aminoacid of formula IV can also be separated in the form of thecorresponding amino acid by carrying out an enzymatic hydrolysis of theracemic mixture with a stereoselective enzyme such as alphachymotrypsin,a method which is described especially in Journal of Biochemistry 19,877-881 (1971).

The salts of the compounds of formula I are prepared by reacting thechosen acids with the amidine of formula I, in a solvent; the saltsobtained are isolated after distillation of the solvent or addition of anon-solvent in order to precipitate them.

The compounds of formula I and their pharmaceutically acceptable saltsbind to the biological receptors of neuropeptide Y (NPY), a 36-aminoacid peptide whose physiological activities are many, especially in thecentral nervous or cardiovascular system. NPY regulates psychomotoractivity, anxiety and sedation, it is a stimulant of food intake; itplays a role in depression, memorization processes, certain sexualbehaviours and epilepsy; it inhibits the secretion of insulin, glucagonand luteinizing hormone; it acts in the kidneys and especially on therenin-angiotensin system; finally, it is a potent vasoconstrictor.Reference can be made to a review published in Drugs of the Future 17(1) 39-45 (1992) which also mentions potential therapeutic activities ofthe antagonists of NPY.

The affinity of the compounds of the invention for the NPY receptors canbe demonstrated in vitro using the method described by Unden et al., inEur. J. Biochem 145 525-530 (1984) on rat cortex membranes; under theseconditions, the compounds of the invention which are exemplifiedhereinafter have IC₅₀ values (concentration inhibiting 50% of thebinding of NPY to its receptor) of between 10 nM and 10 μM, whereas thatfor NPY is 0.5 nM.

Affin compounds may be agonists or antagonists of the action of thepeptide NPY on its receptor.

The antagonistic activity of NPY can be demonstrated by applying themethod described in Proc. Soc. Exp. Biol. Med. 64 453-455 (1947) inpithed rats; under these conditions, the administration of NPY has ahypertensive effect which is reduced or even suppressed when the animalsare treated with am antagonist of the invention.

For the compounds having a strong affinity for the receptors, ID₅₀values of a few μg/kg have been measured during i.v. perfusions of 10μg/kg of NPY.

Currently, no specific antagonist, of high affinity and competitive, isknown and the compounds according to the invention are particularlyvaluable; they can be advantageously used as antihypertensive agents orfor the treatment of angina pectoris especially for their vasodilatingactivity, or for combating coronary and cerebral vasospasms, as well asin the treatment of atherosclerosis and congestive heart failure. Thesecompounds can also be used as anorectic agents, antidepressants ortranquilizers, for reducing anxiety or regulating certain sexualbehaviour disorders. They will also be of real interest in the treatmentof inflammation, allergy certain gastrointestinal disorders, such asCrohn's disease or the regulation of the food intake or alternatively inthat of excess fats, given lipolytic activity; they are also immunemodulators.

They may be used in all the pathologies or disorders NPY dependent.

Thus, the invention also relates to the pharmaceutical compositionscomprising as active ingredient one of the enantiomers of the compoundsof formula I, one mixture thereof or their salts with a pharmaceuticallyacceptable acid, as well as an excipient suitable for administration bythe oral route, by injection or by the transdermal route. The dailydoses will depend on the pathology to be treated and on the patient.

The invention relates to pharmaceutical compositions containing atherapeutically effective amount of a compound according to theinvention or any pharmaceutically acceptable salt thereof and suitableexcipients.

Said excipients are selected depending on the pharmaceutical formulationand the desired route of administration.

In the pharmaceutical compositions of the invention, designed for oral,sublingual, subcutaneous, intramuscular, intravenous, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredients of the above formula (I) or any salt thereof may beadministered to animals and human beings in single dose mixed withconventional pharmaceutical carriers for the treatment or prophylaxis ofthe above disorders or pathologies.

Suitable single-dose forms of administration comprise oral forms such astablets, gelatin capsules, powders, granules, oral solutions orsuspensions, as well as forms for sublingual, buccal, intratracheal,intranasal administration, forms for subcutaneous, intramuscular orintravenous administration and forms for rectal administration.

For local administration, the compounds of the invention may beformulated as creams, ointments or lotions.

In order to ensure the desired prophylactic or therapeutical effect, thedosage of active ingredient may vary from 0.01 to 50 mg per kg of bodyweight and per day.

Each single dose may comprise from 0.5 to 1000 mg, preferably from 1 to500 mg of active ingredient in association with a pharmaceuticalcarrier. Said unit dose may be administered 1 to 5 times per day so asto administer from 0.5 to 5000 mg per day, preferably from 1 to 2500 mg.

Where a solid composition is prepared, such as tablets, the main activeingredient is mixed with a pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, gum-arabic and the like;tablets may be coated with sucrose, a cellulose derivative or othersuitable materials or alternatively they may be treated in such a waythat they have sustained or delayed activity and release a predeterminedamount of active ingredient continuously.

A preparation in gelatin capsules is obtained by mixing the activeingredient with a diluent and poring the resulting mixture in soft orhard gelatin capsules.

A preparation in the form of a syrup or elixir as well as preparationsfor the administration of drops may contain the active ingredienttogether with a sweetener preferably one having negligible calorificvalue, methylparaben and propylparaben as antiseptic agent as well as aflavouring agent and a suitable colouring.

The water-dispersible powders or granules may contain the activeingredient in admixture with dispersing agents, wetting agents,suspending agents such as polyvinylpyrrolidone, as well as sweeteners orflavour correctors.

For the rectal administration, suppositories are used which are preparedwith binding agents which melt at rectal temperature such as cocoabutter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic salinesolutions or sterile injectable solutions are used containingpharmaceutically acceptable dispersing agents and/or wetting agents suchas propylene glycol or butylene glycol.

The active ingredient may also be formulated in the form ofmicrocapsules, where appropriate with one or more carriers or additives.

The compositions of the invention may contain together with thecompounds of the above formula (I) or a pharmaceutically acceptable saltthereof, other active ingredients which may be useful for the treatmentof the above mentioned disorders or pathologies.

The compounds in which Z₁ represents a (C₄ -C₉)alkylene and Q₁ is bondedto Z₁ via a nitrogen atom and represents an amino, guanidino or amidinogroup, whether they are substituted or otherwise, are particularlypreferred; on the other hand, the compounds in which NR₃ R₄ representspyrrolidinyl are preferred.

Compounds (I) in which Z₁ represents methylenecyclohexylmethylene, Q₁represents amino, alkylamino or dialkylamino, R₃ and R₄ form with thenitrogen atom to which they are bound pyrrolidinyl, Ar₂ representsphenyl or methoxyphenyl, Ar₁ represents naphtyl and Q₁, Q₃ R₁, R₂ andR'₂ are such as defined in (I) are more particularly preferred.

In the following text, examples of the compounds of the invention andpreparation processes are described. First, the preparation of a numberof intermediate compounds for synthesis is indicated by way ofillustration.

The compounds of formula I contain in general two asymmetric carbons andcan be isolated in the form of a mixture of two diastereoisomericracemic pairs whose relative proportions will depend on the operatingconditions, given their different physical properties. When the startingmaterials which contain an asymmetric carbon are not racemic mixturesbut are enriched with one or the other of the enantiomers, the finalproduct will in general not be a mixture of two racemates except if theoperating conditions result in racemization.

In the products of formula I described hereinafter, the relativeproportions of the two racemic pairs are measured by conventionalmethods such as high-performance liquid chromatography or nuclearmagnetic resonance spectroscopy.

Unless otherwise stated, the isolated nitriles of formula II are anequimolar mixture of diastereoisomers.

A--Preparation of sulphonamides

N-(2-naphthylsulphonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid.

46.8 ml of a N aqueous NaOH solution are introduced into a suspension of5 g of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride in150 ml of dioxane followed, slowly, by 5.3 g of 2-naphthalenesulphonylchloride and a N NaOH solution in order to maintain a pH in the vicinityof 10. At the end of the addition, the mixture is kept stirring for 3hours at around 20° C. before the addition of 150 ml of CH₂ Cl₂. Afteracidification of the aqueous phase up to pH 2, the organic phase isseparated and the aqueous phase is reextracted with 150 ml of CH₂ Cl₂.The organic phases are dried, concentrated and the residue is purifiedby silica gel chromatography, eluting with a mixture of methylenechloride and methanol (80/20-V/V). 7 g of sulphonamide are obtained inthe form of a hemihydrate, m.p.=110° C.

N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosine.

5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, withstirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 mlof CH₂ Cl₂ and 50 ml of a saturated aqueous potassium carbonatesolution. After one night, the solid is removed, the organic phaseseparated and the aqueous phase reextracted with CH₂ Cl₂. The driedorganic phases are concentrated and the residue is chromatographed on asilica column, eluting with a mixture of CH₂ Cl₂ and CH₃ OH (95/5-V/V).6.8 g of racemic ethylN-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, whichproduct melts at 99° C. This ester is hydrolysed in 100 ml of C₂ H₅ OHcontaining 9.5 ml of a 5N aqueous KOH solution to give, afteracidification, 5.5 g of the corresponding acid which melts at 183° C.

The following are prepared in the same manner:

N-(2-naphthylsulphonyl)phenylalanine

m.p.=146° C. (methyl ester: m.p.=144° C.)

N-(2-naphthylsulphonyl)-O-methyltyrosine

m.p.=174° C. (ethyl ester: m.p.=138° C.)

N-methyl-N-(2-naphthylsulphonyl)phenylalanine

m.p.=122° C. (methyl ester: m.p.=106° C.)

N-(2-naphthylsulphonyl)-2-amino-2-indancarboxylic acid

m.p.=264° C.

N-(5-isoquinolylsulphonyl)-alpha-methylphenylalanine

(ethyl ether m.p.=60° C.)

N-(8-quinolinylsulphonyl)-O-methyltyrosine

m.p.=228° C.

N-(2-naphthylsulphonyl)-O-benzyltyrosine

m.p.=182° C.

N-(1-naphthylsulphonyl)-2,4-dimethylphenylalanine

m.p.=220° C. (ethyl ester: m.p.=134° C.)

N-(4-tolylsulphonyl)-4-chlorophenylalanine

m.p.=164° C. (ethyl ester m.p.=114° C.

The starting ethyl 2-amino-2-indancarboxylate can be prepared from ethylN-diphenylmethyleneglycinate: at -70° C., 25 g of ethylN-diphenylmethyleneglycinate are introduced into 1500 ml oftetrahyrofuran containing 10.5 g of potassium tert-butoxide, followed,slowly, by 12.6 ml of α,α-(dibromo)-ortho-xylene and, after 12 hours, by10.5 g of potassium tert-butoxide. The mixture is allowed to return toroom temperature and after 12 hours, a saturated aqueous NH₄ Cl solutionis introduced into the medium. The solvents are removed by distillationunder reduced pressure and the residue is extracted with (C₂ H₅)₂ O. Theseparated organic phase is stirred for 16 hours, at room temperature,with 150 ml of a N aqueous HCl solution. The aqueous solution, after 3washes with (C₂ H₅)₂ O, is adjusted to pH 8 by addition of NaHCO₃ and13.4 g of the desired ester are extracted therefrom in CH₂ Cl₂.

m.p.=56° C.

B. Preparation of (4-cyano)phenylalanylamides

1. Ethyl ester of (4-cyano)phenylalanine.

7.23 g of tetrabutylammonium bromide, 93 g of Na₂ CO₃ and then 60 g ofethyl N-(diphenylmethylene)glycinate are introduced into a solution of40.4 g of 4-(bromomethyl)benzonitrile in 460 ml of anhydrous CH₃ CN. Themedium is maintained for 4 hours at its reflux temperature and than thesolids are separated and the solvents removed by distillation underreduced pressure. The residue is taken up in 1 liter of (C₂ H₅)₂ O andthen, after filtration, concentrated to 500 ml before adding 300 ml of aN aqueous HCl solution to it. After stirring for 16 hours, the mixtureis decanted and the pH of the separated aqueous phase is adjusted toaround 8. The final product is extracted therefrom in CH₂ Cl₂. 34.8 g ofester are obtained in an oily form of which the hydrochloride melts at170° C.

2. Separation of the laevorotatary and dextrorotatory isomers of thepreceding ester by enzymatic hydrolysis.

10 g of racemic ester, 20 mg of alphachymotrypsin and 0.9 g of bovineserum albumin are stirred for 16 hours at around 25° C., in 1 l of a0.1M aqueous CH₃ COONa solution whose pH is adjusted to between 6.5 and6.8 by addition of a 0.1N aqueous NaOH solution. After filtration of themedium on talc and than on activated carbon, half of the solvant isremoved by distillation under reduced pressure at around 35° C. and theremaining aqueous solution is adjusted to pH 8 by addition of NaOH, andthen extracted with CH₂ Cl₂. After the usual treatments of the organicphase, 4.5 g of oily laevorotatary ethyl2-amino-3-(4-cyanophenyl)propionate are obtained.

    [α].sub.D.sup.20 =-27° C. (c=1;CH.sub.3 OH)

The basic aqueous solution contains the sodium salt of the acidcorresponding to the other enantiomer. After acidification up to pH 4followed by freeze-drying, a white powder is isolated which contains thelaevorotatary amino acid

3. N-(t-butoxycarbonyl)-4-cyanophenylalanine.

20 ml of N aqueous NaOH solution and 4.34 g of di-(tert-butyl) carbonateare introduced at 5° C. into a solution of 4.34 g of an ethyl ester of4-cyanophenylalanine in 70 ml of dioxane. After returning to roomtemperature and 3 hours of stirring, the reaction medium is concentratedto dryness; 100 ml of water is then poured over the residue and afterwashing with CH₃ COOC₂ H₅, the aqueous solution is adjusted to pH 2 byaddition of a KHSO₄ solution; the final product is then extracted fromCH₂ Cl₂.

4. 1-[2-amino-3-(4-cyanophenyl)]propionylpyrrolidine.

1.98 g of pyrrolidine and 3 g of hydroxybenzotriazole are introduced, at0° C., into 70 ml of CH₂ Cl₂ containing 5.4 g ofN-(t-butoxycarbonyl)-4-cyanophenylalanine, followed at around -5° C. bya solution of 4 g of dicyclohexylcarbodiimide in 30 ml of CH₂ Cl₂. Afterstirring for 16 hours at 20° C., the organic phase is filtered andwashed with a saturated aqueous Na₂ CO₃ solution and then with a KHSO₄solution of pH 2 and finally with water. After the usual treatments,4.73 g of the desired derivative is obtained whose primary amine groupis protected by a t-butoxycarbonyl group; this group can be removed bythe action of an acid: the compound is dissolved in 50 ml of ethylacetate and 50 ml of an ethyl acetate solution saturated at 15° C. withHCl are added at around 0° C.; after stirring for 2 hours at around 20°C., the solvent is removed and the hydrochloride of the desired productis obtained.

The racemic hydrochloride melts at 224° C.

The enantiomer, prepared from the laevorotatary ester, is laevorotatary:

    [α].sub.D.sup.20 =-68°8 (c=1; CH.sub.3 OH)

whereas that prepared from the laevorotatary residual amino acid isdextrorotatory, under the same measurement conditions.

5. 1-[2-amino-3-(4-cyanophenyl)]propionyl piperidine.

The racemic hydrochloride melts at 218° C.; the intermediate compoundN-(t-butoxycarbonyl) melts at 132° C.

6. [N-methyl-N-ethyl]-2-amino-3-(4-cyanophenyl)propionamide.

The racemic hydrochloride melts at 228° C.

C. Preparation of the compounds of formula II

1. By reaction of a sulphonamide and a (4-cyano)phenylalanylamide.

1.1-(2-[2-(3,4-dichlorophenylsulphamoyl)-3-(4-methoxyphenyl)propionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 1) ##STR10##

2.5 g of N-(3,4-dichlorophenylsulphonyl)-O-methylthyrosine, 1,82 g of1-[2-amino-3-(4-cyano)phenylpropionyl]pyrrolidine hydrochloride and 2.87g of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP) are introduced into 100 ml of acetonitrile, at0° C., followed by 1.75 ml of triethylamine at a temperature of lessthan 5° C. After stirring for 16 hours at room temperature at around 20°C., the solvent is removed under reduced pressure and the residue isdissolved in 80 ml of CH₃ COOC₂ H₅. After washing the organic phase withan aqueous solution at pH 2, with a saturated NaHCO₃ solution and withwater, the solvent is removed by distillation and the residue ischromatographed on a silica gel column, eluting with a CH₂ Cl₂ /CH₃ OHmixture (98/2-V/V). 2.9 g of a mixture of diastereoisomers of thenitrile are obtained, which mixture melts at 101° C.

The following are obtained in the same manner:

N-ethyl-N-methyl-2-[2-(3,4-dichlorophenylsulphamoyl)-3-(4-methoxyphenyl)propionamido]-3-(4-cyanophenyl)propionamide(compound 2).

m.p.=192° C., crystallized with 1.5 H₂ O

1-(2-[2-(2-naphthylsulphamoyl)-3-(4-methoxyphenyl)propionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 3)

Prepared from racemic sulphonamide and laevorotatary1-[2-amino-3-(4-cyanophenyl)propionyl]pyrrolidine hydrochloride.

m.p.=135° C., crystallized with 1.5 H₂ O

1-(2-[2-(2-naphthylsulphamoyl)-3-phenylpropionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 4)

m.p.=206° C., crystallized with H₂ O

1-(2-[2-(2-naphthylsulphamoyl)-3-phenylpropionamido]-3-(4-cyanophenyl)propionyl)piperidine(compound 5)

m.p.=210° C., crystallized with H₂ O

N-ethyl-N-methyl-2-[2-(1-naphthylsulphamoyl)-3-(3,4-dichlorophenyl)propionamido]-3-(4-cyanophenyl)propionamide(compound 6).

m.p.=182° C., crystallized with 0.5 H₂ O

N-(2-naphthylsulphonyl)-3-[1-(pyrrolidinylcarbonyl)-2-(4-cyanophenyl)ethylaminocarbonyl]tetrahydroisoquinoline(compound 7)

m.p.=232° C., crystallized with 0.75 H₂ O

1-(2-[(2-(2-naphthylsulphamoyl)-2-indanyl)carboxamido]-3-(4-cyanophenyl)propionyl)piperidine(compound 8)

m.p.=224° C., crystallized with H₂ O##STR11##1-(2-[2-(8-quinolylsulphamoyl)-3-(4-methoxyphenyl)propionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 9)

Prepared from the racemic sulphonamide and the laevorotatary1-[2-amino-3-(4-cyanophenyl)]propionylpyrrolidine hydrochloride

m.p.=175° C., crystallized with 1.5 H₂ O

1-(2-[2-(2-naphthylsulphamoyl)-3-(4-benzyloxyphenyl)propionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 10)

m.p.=110° C., crystallized with 1 H₂ O

2. By a coupling reaction of an alpha-amino acid with a(4-cyanophenyl)alanylamide followed by reaction with the sulphochloride.

2.1.1-(2-[2-(2-naphthylsulphamoyl)-3-phenylpropionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 4 and compound 4A).

a) 1.75 g of N-(t-butoxycarbonyl)phenylalanine, 0.95 ml ofN-ethylmorpholine, 3.34 g of BOP and 1.75 g of1-(2-amino-3-(4-cyanophenyl)propionyl)pyrrolidine hydrochloride areintroduced, at 0° C., into 20 ml of CH₃ CN, followed by 1.6 ml ofN-ethylmorpholine. After stirring for 16 hours at room temperature, thesolvent is removed by distillation under reduced pressure and theresidue is dissolved in CH₃ COOC₂ H₅, in the presence of a saturatedNaHCO₃ solution. The organic phase, washed in the usual manner anddried, is concentrated under reduced pressure and the residue ispurified by chromatography on a silica gel column, eluting with CH₂ Cl₂/CH₃ OH (98/2-V/V).

The product obtained is dissolved in 50 ml of CH₂ Cl₂ and, at 0° C., 50ml of CF₃ COOH are added. When the medium has returned to roomtemperature, it is stirred for another 30 minutes and then the volatileproducts are removed by distillation under reduced pressure; afteraddition of 40 ml of water, the mixture is freeze-dried to give 2.9 g oftrifluoroacetate.

b) 1.75 ml of N-ethylmorpholine are slowly introduced, at 0° C., into 35ml of a solution of 2.3 g of the preceding trifluoroacetate in CH₂ Cl₂,followed by 1.1 g of 2-naphthalenesulphonyl chloride in solution in 10ml of CH₂ Cl₂. After stirring for 4 hours at room temperature, theorganic phase is washed with a 0.1N aqueous HCl solution and then withwater. The residue obtained after distillation of the solvent ischromatographed on silica gel, eluting with a CH₂ Cl₂ /CH₃ OH mixture(95/5-V/V) to give 1.95 g of the expected compound 4.

When the two starting materials are pure enantiomers, only one of thefour stereoisomers of compound 4 is obtained under these conditions.

The product (compound 4A) prepared from the two laevorotataryenantiomers previously described, crystallized with 0.25 H₂ O, melts at118° C.

    [α].sub.D.sup.20 =-19°5 C (c=1; DMSO)

The following are obtained by the same reaction sequence:

starting with N-(t-butoxycarbonyl)-L-phenylalanine and the hydrochlorideof laevorotatory 1-[2-amino-3-(4-cyanophenyl)propionyl]pyrrolidine, thecompound 4B.

    [α].sub.D.sup.20 =+15°5 C (c=1 DMSO)

starting with N-(t-butoxycarbonyl)-O-methyl-D-tyrosine and thehydrochloride of laevorotatory1-[2-amino-3-(4-cyanophenyl)propionyl]pyrrolidine, hydrated1-(2-[2-(2-naphthylsulphamoyl)-3-(4-methoxyphenyl)propionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 3A)

m.p.=143° C.

    [α].sub.D.sup.20 =+4°1 C (c=1; CH.sub.3 OH)

starting with N-(t-butoxycarbonyl)-D-phenylalanine and the hydrochlorideof dextrorotatory 1-[2-amino-3-(4-cyanophenyl)propionyl]pyrrolidine,1-(2-[2-(5-dimethylamino-1-naphthylsulphamoyl)-3-phenylpropionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 11)

m.p.=116° C.

    [α].sub.D.sup.20 =-4°5 (c=1; DMSO)

starting with the racemic mixtures,1-(2-[2-(1-naphthylsulphamoyl)-3-(2-thienyl)propionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 12)

m.p.=121 ° C.

2.2.1-(2-[(N-(2-naphthylsulphamoyl)-5-methoxy-2-indolyl)carboxamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 13).

a) 1.3 g of 5-methoxy-2-indolecarboxylic acid, 3.16 g of BOP and 2 g of1-(2-amino-3-(4-cyanophenyl)-propionyl)pyrrolidine hydrochloride areintroduced, at 0° C., into 100 ml of CH₃ CN, followed by 2.5 ml oftriethylamine.

After stirring for 16 hours at room temperature,1-(2-[(5-methoxy-2-indolyl)carboxamido]-3-(4-cyanophenyl)propionyl)pyrrolidineis filtered washed with ether and dried.

m.p.=204° C.

b) 0.23 g of a 60% suspension of sodium hydride in oil is added, at 0°C., to a suspension of 2.2 g of the preceding product in 100 ml of THF.

After stirring for 1 hour at 5° C., 1.3 g of 2-naphthalenesulphonylchloride in solution in 20 ml of THF are added at around 0° C. and themixture is stirred at room temperature for 16 hours and then at around50° C. for 3 hours. The precipitate is filtered and the filtrate isevaporated under reduced pressure. The residue is chromatographed on asilica column, eluting with CH₂ Cl₂ /cyclohexane (70/30-V/V) to give theexpected hemihydrate product which melts at 186° C.

In the same manner, starting with 2-indolecarboxylic acid,1-(2-[(N-(2-naphthylsulphamoyl)-2-indolyl)carboxamido]-3-(4-cyanophenyl)propionyl)pyrrolidine is isolated (compound 14)

m.p.=180° C.

3. By substitution of a sulphonamide of formula II in order to obtain acompound in which R₁ is different from H.

1-(2-[2-(N-methyl-2-naphthylsulphamoyl)-3-phenylpropionamido]-3-(4-cyanophenyl)propionyl)pyrrolidine(compound 15)

2 g of compound 4 are dissolved in 20 ml of dimethylformamide at 0° C.and 0.475 g of K₂ CO₃ and 0.214 ml of ICH₃ are added. After 24 hours at5° C., 20 ml of H₂ O and 40 ml of CH₂ Cl₂ are added. The organic phasedecanted is washed, dried and concentrated to dryness. The residue isrecrystallized from (CH₃)₂ CHOH to give 1.76 g of final product whichmelts at 186° C.

The enantiomer prepared from compound 4A described in C-2 isdexrorotatory.

    [α].sub.D.sup.20 =40° C. (c=1; CH.sub.3 OH)

4. By reaction of a sulphonamide and an ester of 4-cyanophenylalaninefollowed by a saponification and an acylation.

1-(2-[2-(4-methylphenylsulphamoyl)-3-(4-chlorophenyl)propionamido]-3-(4-cyanophenyl)propionyl)hexahydroazepine(compound 16).

a) 4 g of N-(4-tolylsulphonyl)-4-chlorophenyl)alanine and 4.1 g of4-cyanophenylalanine ethyl ester hydrochloride are reacted under theconditions described in § (C.1) and 3.7 g of ethyl2-(2-(4-tolylsulphamoyl)-3-(4-chlorophenyl)propionamido)-3-(4-cyanophenyl)propionatewhich melts at 82° C. are obtained by the usual treatments.

This ester is hydrolysed by a solution of 1 g of KOH in a mixture of 10ml of water and 20 ml of ethanol to give, after acidification, 2.5 g ofthe corresponding acid which melts at 104° C.

b) 2 g of B.O.P. and 1.6 ml of N-ethylmorpholine are added, at 0° C., toa solution of 2.5 g of the preceding acid in 80 ml of CH₃ CN, followedby 0.5 g of hexamethyleneimine. After stirring for 16 hours at around20° C., the solvent is evaporated. The residue is dissolved in CH₂ Cl₂.The organic phase is washed in the usual manner, dried and thenconcentrated under reduced pressure.

After silica gel chromatography, eluting with a CH₂ Cl₂ /CH₃ OH mixture(V/V:95/5), 1.3 g of the expected product is obtained.

m.p.=194° C.

(2-[2-(1-naphthylsulphamoyl)-3-(2,4-dimethylphenyl)propionamido]-3-(4-cyanophenyl)propionyl)dimethylaminehemi-hydrated (confound 17) is prepared in the same manner.

m.p.=140° C.

D. Preparation of imidoesters, Intermediates in the Preparation ofAmidines from the Nitriles

1. Starting with compound 5 and C₂ H₅ OH.

2 g of compound 5 are rapidly introduced into 20 ml of anhydrous C₂ H₅OH saturated at 0° C. with HCl. After stirring overnight, at atemperature of between 0° C. and 5° C., the solvent is removed bydistillation at a temperature of less than 25° C., to yield thehydrochloride of the desired product.

2. Starting with compound 4 and CH₃ OH.

5 g of compound 4 are rapidly introduced into 100 ml of anhydrous CH₃ OHsaturated at 0° C. with HCl. After stirring overnight at around 0° C.,the solvent is removed by distillation at a temperature of less than 22°C., in order to isolate the hydrochloride of the imidoester.

In order to obtain the corresponding base, the hydrochloride isdissolved in 100 ml of CH₂ Cl₂ and then triethylamine is added at around5° C. until a pH of 7.5 (measured in aqueous medium) is obtained. Theorganic phase is then washed 5 times with 30 ml of water at around 20°C., dried and concentrated to give 5.2 g of imidoester.

The structural formulae and the physico-chemical characteristics of theproducts prepared as described in the following examples are presentedin Table I; A/B represents the relative proportions of the 2 racemates.

Example 1

2 g of the hydrochloride of the imidoester of compound 5, preparedaccording to D-1, are dissolved in 20 ml of anhydrous isopropanol and1.6 ml of n-propylamine are introduced into the solution. After stirringfor 2 hours, the solvent is removed and the residue is chromatographedon silica gel, eluting with a CH₂ Cl₂ /CH₃ OH mixture (9/1-V/V). 1.7 gof the hydrochloride of the expected product are thus obtained.

Example 2

1 g of the hydrochloride of the imidoester of compound 5, preparedaccording to D-1, are dissolved in 10 ml of anhydrous C₂ H₅ OH. 0.14 mlof 1,2-ethanediamine is added and the medium is maintained at around 70°C. for 1 hour 30 minutes. The solvent is removed under reduced pressureand the residue is purified by silica gel chromatography, eluting with aCH₂ Cl₂ /CH₃ OH mixture (92/8-V/V).

Example 3

2.1 ml of triethylamine and 0.33 ml of 1-aminopentanol are added, at 5°C., to a solution of 2 g of the hydrochloride of the imidoester ofcompound 4, prepared according to D-1. After stirring for 16 hours atroom temperature, the solvent is evaporated under reduced pressure andthe residue is chromatographed on silica gel, eluting with a CH₂ Cl₂/CH₃ OH mixture (9/1-V/V) to yield 1.5 g of hydrochloride.

Example 4

3.5 ml of triethylamine and 2.2 g ofN-(t-butyloxycarbonyl)-1,3-propanediamine are introduced, at 5° C., intoa solution of 4.5 g of the hydrochloride of the imidoester of compound4. After 20 hours at room temperature, the solvent is removed bydistillation under reduced pressure and the residue is dissolved in 50ml of CH₂ Cl₂. The organic solution is washed with a 0.1N aqueous NaOHsolution, and then with water and dried. The residue obtained afterconcentration crystallizes from a mixture of [(CH₃)₂ CH]₂ O and CH₃COOC₂ H₅ to give 2.5 g of the desired product.

Example 5

40 ml of CH₃ COOC₂ H₅, saturated with HCl, are introduced, at 5° C.,into a solution of 4 g of the product obtained in Example 4 in 40 ml ofCH₃ COOC₂ H₅. After 2 hours at around 20° C., the precipitate isisolated, washed with CH₃ COOC₂ H₅ and then dissolved in a mixture of 40ml of CH₂ Cl₂ and 20 ml of 0.5N aqueous NaOH solution. After stirringfor 16 hours at around 20° C., the organic phase is separated and it istreated in the usual manner to yield 2.1 g of the expected product afterrecrystallization from a mixture of CH₃ COOC₂ H₅ and CH₃ OH.

Example 6

2 g of the imidoester of compound 4A, prepared according to D-2, areintroduced into 30 ml of anhydrous CH₃ OH and 0.82 g oftrans-4]N-(t-butoxycarbonyl)aminomethyl]cyclohexylmethylamine is addedfollowed by a few drops of CH₃ OH, saturated with HCl, until a pH of 8(measured in water) is obtained.

After 52 hours at room temperature, the CH₃ OH is evaporated, 30 ml ofCH₂ Cl₂ are added to the medium, and then it is removed under reducedpressures the residue obtained is introduced, at 5° C., into 30 ml ofCH₃ COOC₂ H₅, saturated at 15° C. with HCl. After returning to roomtemperature, it is kept stirring for half an hour and then the solventis removed before purifying the residue by silica gel chromatography,eluting with a CH₂ Cl₂ /CH₃ OH mixture (80/20-V/V).

After recrystallization from 1-propanol, 1.8 g of the product mentionedin Table I are isolated.

Example 7

a) (N, N-dimethyl)-4-[aminomethyl]cyclohexylmethylamine (trans)

63.6 ml of an N aqueous NaOH solution and 1.28 g of MgO are introduced,at 0° C., into 50 ml of dioxane containing 5 g oftrans-4-(aminomethyl)cyclohexylcarboxylic acid, followed, slowly, by6.94 g of di(t-butyl)carbonate in solution in 20 ml of dioxane. After 20hours at room temperature, the mixture is filtered, the solvent isremoved and the residue is taken up in 100 ml of H₂ O and the aqueousphase is washed with (C₂ H₅)₂ O before acidifying it up to pH 2 byaddition of KHSO)₄ ; it is then extracted in CH₃ COOC₂ H₅ to yield 7.3 gof trans-N-(t-butoxycarbonyl)-4-(aminomethyl)cyclohexylcarboxylic acidwhich melts at 125° C.

This compound is then dissolved in a mixture of 20 ml of CH₂ Cl₂ and 25ml of (CH₃)₂ NCHO, into which 4.8 g of hydroxybenzotriazole areintroduced, followed by 6.15 g of N,N'-dicyclohexylcarbodiimide insolution in 50 ml of CH₂ Cl₂. After stirring for 2 hours, 4 g ofanhydrous (CH₃)₂ NH are added and the mixture is kept stirring for 16hours. The precipitate is then separated, the organic phase is washedseveral times with a saturated aqueous NaHCO₃ solution and then withwater. After drying, concentration and chromatography of the residue ona silica gel, eluting with CH₃ COOC₂ H₅, 5.8 g oftrans-N,N-dimethyl-N'-(t-butoxycarbonyl)-4-(aminomethyl)cyclohexylcarboxamideare isolated, which product melts at 94° C.

This compound is dissolved in 50 ml of CH₃ COOC₂ H₅ saturated with HCland after one hour, the hydrochloride precipitate which appears isfiltered, which precipitate, when treated with a base, gives 3.5 g oftrans-N,N-dimethyl-4-(aminomethyl)cyclohexylcarboxamide in the form ofan oil.

This oil is dissolved in 10 ml of tetrahydrofuran into which 25 ml of 1MLiAlH₄ solution in the same solvent are then introduced at 0° C. Afterstirring for 16 hours at room temperature, the mixture is cooled to 0°C. and 0.9 ml of ice-cold water is added followed by 2.7 ml of a 15%(w/V) aqueous NaOH solution and finally by 0.9 ml of water. Theprecipitate is removed and the solvent is evaporated by distillationunder reduced pressure to give the expected diamine which distils at 60°C. under 1 Pa.

b) By reacting trans-(N,N-dimethyl)-4-(aminomethyl)cyclohexylmethylamineand the imidoester of compound 4A, according to the procedure describedin Example 3, the pure enantiomer described in Table I is obtained afterrecrystallization from isopropanol.

Preparation of the Compound of Example 46 from that of Example 38

0.08 g of aminoiminomethanesulphonic acid and 0.1 ml of triethylamineare added, under an inert atmosphere, to a solution of 0.5 g of compound38 in 10 ml of anhydrous methanol. After 16 hours at about 20° C., thesolvent is evaporated and the residue is taken up in 20 ml of 1N aqueousNaOH solution at a temperature in the vicinity of 0° C. and extractedwith dichloromethane. The organic phase is dried, concentrated and theresidue is chromatographed on a silica column, eluting withdichloromethane/methanol (9/1-V/V) and then with a methanol/aqueoussolution of concentrated NH₄ OH mixture (7/3-V/V). Afterrecrystallization from an ethanol/ethyl acetate mixture (8/2-V/V), theexpected product is isolated in the form of a base whose dihydrochlorideis prepared by the action of HCl in ethanol. m.p.=185° C. (2 HCl, H₂ O).

Following the general procedure described in example 3, and startingfrom the appropriate amines, compound 20 is prepared from compound 4A,compound 60 is prepared from compound 4B, compound 58 is prepared fromcompound 3A, compound 64 is prepared from compound 10.

Following the procedure described in example 6 and starting from theappropriate amines compounds 45, 47 and 48 are prepared from compound4A.

Example 61

a) N-(butyloxycarbonyl)-4-(aminomethyl)cyclohexylmethylamine (cis).

1.6 g of potassium tert-butoxide are added, at 0° C., in portions, to asolution of 2 g of cis-1,4-[dimethylamino]cyclohexane dihydrochloride(obtained according to the method described in Bar. 71 B, 759 (1938)) in70 ml of anhydrous methanol, followed by a solution of 2.1 g ofdi-tert-butyl dicarbonate in 100 ml of methanol.

The mixture is heated for 16 hours at around 35° C., the precipitate isfiltered and the solvent is evaporated under reduced pressure. Theexpected product is isolated by silica column chromatography, elutingwith CH₂ Cl₂ /MeOH: 95/5 followed by 80/20 (V/V)

m.p.=201° C.

b) By reacting the preceding amine with 2 g of the imidoester ofcompound 4A prepared according to D-2 under the conditions described inExample 6, the expected product is obtained which is dissolved in 15 mlof HCl, filtered and then extracted from the aqueous phase with 3 times7 ml of butanol. The solvent is evaporated under reduced pressure. Theresidue is taken up in water and freeze-dried to give the pureenantiomer described in Table I.

Example 67

a) 4-(N,N-dimethylaminomethyl)cyclohexylmethylamine, cis

-cyclohexyl-1,4-dimethanol, cis

328 ml of a 1M solution of LiAlH₄ in tetrahydrofurane are added slowly,at 0° C., to a solution of 66 g of ethyl cyclohexyl-1,4-dicarboxylate,cis in 500 ml THF.

The mixture is stirred for 16 hours at room temperature and then cooledat about 0° C. 13 ml of water, 39 ml of an aqueous solution of 15% NaOH(w/w) and then 13 ml of water are successively added to the mixture.

Salts are filtered out, the solvent is evaporated under pressure and theresidue is distilled at 120°-124° C. under reduced 45.10⁻⁶ bar (4.5 Pa).37 g of the expected product are obtained.

-cyclohexyl-1-4-diparatoluene sulfonate (cis)

A solution of 41 g of paratoluene sulfonyl chloride and 28 mltriethylamine in 35 ml tetrahydrofurane are added, at 0° C., to asolution of the preceding alcohol in 70 ml of tetrahydrofurane.

The mixture is stirred at 25° C. for 24 hours and next heated at 50° C.for 3 hours.

After cooling, 50 ml of a saturated NaCl solution and 50 ml of a HClsolution about 1N are added to the reaction mixture. The solvent isevaporated under reduced pressure and the residue is taken up in 300 mlether, 200 ml 2N NaOH and the resulting mixture is kept stirring for 16hours at room temperature.

After decantation the aqueous phase is extracted with dichloromethane.The organic phases are dried and the solvent is removed by distillationunder reduced pressure. 29 g of the expected product are finallyisolated.

F=91° C.

-4-(N,N-dimethylaminomethyl)cyclohexylmethylamine, cis

14 g of the preceding ditosylate are stirred at 25° C. for 48 hours inan autoclave in a methanolic solution saturated with ammonia. Afterevaporation under reduced pressure, the residue is taken up in CH₂ Cl₂and 1N, HCl.

The resulting mixture is decanted and the aqueous phase is basified with2N, NaOH and then extracted with dichloromethane. After evaporationunder reduced pressure, the residue is purified by silica gelchromatography, eluting with a CH₂ Cl₂ /CH₃ OH mixture (70/30-v/v) 6 gof 4-aminomethylcyclohexyl paratoluene sulfonate, cis are isolated.

The preceding rosylate is then added to a saturated solution ofdimethylamine in methanol and then heated at 70° C. for 20 hours in anautoclave.

After evaporation under reduced pressure, the residue is taken up in CH₂Cl₂ and 2 ml of water. 2 g of solid KOH are added to the mixture.

The organic phase is then dried and then concentrated in vacuo. Theexpected dihydrochloride is isolated from a saturated solution ofhydrochloric acid in ethanol; m.p. 252° C.

b) compound 67

0.9 g of the preceding dihydrochloride are reacted with 2.4 g of thedihydrochloride of the imidoester of compound 4A and 1.2 ml ofN-ethylmorpholine in 100 ml methanol. The mixture is stirred at 40° C.for 16 hours, the solvent is then evaporated and the pure enantiomerdescribed in Table I is obtained after treatment according to theprocedure described in example 61 § b.

Example 69

(Case where R₂ and R'₂ form a double bond)1-(2-[N-(2-naphthylsulfamoyl)-2-indolylcarboxamido]-3-(4-(N-[4-(dimethylaminomethyl)-trans-cyclohexylmethyl]-amidino)phenyl)propionyl)pyrrolidine,dihydrochloride, 4H₂ O.

This compound is prepared from compound 14 according to the generalprocedure described in Example 3.

m.p.=230° C.

Example 70

1-(2-[(N-(2-naphthylsulphamoyl)-5-methoxy-2-indolyl)carboxamido]-3-(4-(N-[4-(dimethylaminomethyl)-trans-cyclohexylmethyl]amidino)phenyl)propionyl)pyrrolidine.

This compound is prepared in the same manner from compound 13.

m.p.=230° C.

Compound 18:

1-(2-[2-(5-isoquinolylsulfamoyl)-2-methyl-3-phenyl-propionamido]-3-(4-cyanophenyl)-propionyl)-pyrrolidine.

m.p.=264° C.

This compound is prepared as for compound 16 (see § C.4).

    TABLE 1      ##STR12##       ex. Ar.sub.1 R.sub.1 Ar.sub.2 R.sub.2 NR.sub.3 R.sub.4 Z.sub.1 Q.sub.1 N     Q.sub.2 NQ.sub.3 sel (solvate) F °C. A/B [α].sub.D.sup.20.sp     sp.(1)                     1      ##STR13##      H      ##STR14##      H      ##STR15##      (CH.sub.2).sub.2 CH.sub.3 NH NH HCl, 2,5 H.sub.2 O 210 40/60         2      ##STR16##      H      ##STR17##      H      ##STR18##      rien H N(CH.sub.2).sub.2 N HCl, 2,5 H.sub.2 O 228 45/55     3      ##STR19##      H      ##STR20##      H      ##STR21##      (CH.sub.2).sub.5 OH NH NH HCl, H.sub.2 O 231 60/40      4     ##STR22##      H      ##STR23##      H      ##STR24##      (CH.sub.2).sub.3 NHCOOC(CH.sub.3).sub.3 NH NH Base, 0,5 H.sub.2 O 150     50/50                   5     ##STR25##      H      ##STR26##       H      ##STR27##      rien H N(CH.sub.2).sub.3N Base, 0,5 H.sub.2 O 171 25/75     6      ##STR28##      H      ##STR29##      H      ##STR30##      ##STR31##      NH.sub.2 NH NH      ##STR32##      260 0/100.sup.(2) +19°2      7     ##STR33##      H      ##STR34##      H      ##STR35##      ##STR36##      N(CH.sub.3).sub.2 NH NH 2HCl, 3 H.sub.2      O 225 0/100.sup.(2) +21°4      8     ##STR37##      H      ##STR38##      H      ##STR39##      CH(CH.sub.3) CH.sub.3 NH NH Base, H.sub.2 O 192 40/50      9     ##STR40##      H      ##STR41##      H      ##STR42##      (CH.sub.2).sub.2 CH.sub.3 NH NH HCl, H.sub.2 O 262 30/60      10     ##STR43##      H      ##STR44##      H      ##STR45##      (CH.sub.2).sub.3 CH.sub.3 NH NH HCl, 1/3 H.sub.2 O 270 50/50  11      ##STR46##      H      ##STR47##      H      ##STR48##      (CH.sub.2).sub.3 CH.sub.3 NCH.sub.3 NH Base, 1,5 H.sub.2 O 200 60/40     12      ##STR49##      H      ##STR50##      H      ##STR51##      (CH.sub.2).sub.3 N(CH.sub.3).sub.2 NH NH 2HCl, 0,5 H.sub.2 O 172 50/50                  13      ##STR52##      ##STR53##      H      ##STR54##      (CH.sub.2).sub.3 N(CH.sub.3).sub.2 NH NH HCl, 2H.sub.2 O 184 50/50               14      ##STR55##      H      ##STR56##      H      ##STR57##      (CH.sub.2).sub.4 N(CH.sub.3).sub.2 NH NH HCl, 1,5 H.sub.2 O 265 50/50     15      ##STR58##      H      ##STR59##      H      ##STR60##      ##STR61##      N(CH.sub.3).sub.2 NH NH 2HCl, 6 H.sub.2 O 260 50/50      16     ##STR62##      H      ##STR63##      H      ##STR64##      ##STR65##      N(CH.sub.3).sub.2 NH NH 2HCl, 3 H.sub.2 O 230 50/50      17     ##STR66##      H      ##STR67##      H      ##STR68##      ##STR69##      NH.sub.2 NH NH 2HCl, 4 H.sub.2 O 245 35/65      18     ##STR70##      H      ##STR71##      H      ##STR72##      ##STR73##      N(CH.sub.3).sub.2 NH NH 2HCl, 2 H.sub.2 O 222 50/50      19     ##STR74##      H      ##STR75##      H      ##STR76##      ##STR77##      N(CH.sub.3).sub.2 NH NH 2HCl, 3,5 H.sub.2 O 244 50/50      20     ##STR78##      H      ##STR79##      H      ##STR80##      ##STR81##      N(CH.sub.3).sub.2 NH NH 2HCl, 3 H.sub.2      O 255 0/100.sup.(2) +24°5      21     ##STR82##      H      ##STR83##      H      ##STR84##      (CH.sub.2).sub.3      ##STR85##      NH NH      ##STR86##      190 35/65      22     ##STR87##      H      ##STR88##      H      ##STR89##      (CH.sub.2).sub.2      ##STR90##      NH NH 2HCl, 2 H.sub.2 O 220 65/35      23     ##STR91##      H      ##STR92##      H      ##STR93##      (CH.sub.2).sub.3      ##STR94##      NH NH 2HCl, 2 H.sub.2 O 242 50/50      24     ##STR95##      H      ##STR96##      H      ##STR97##      (CH.sub.2).sub.5      ##STR98##      NH NH 3HCl, 3 H.sub.2 O 240 50/50      25     ##STR99##      CH.sub.3      ##STR100##      H      ##STR101##      (CH.sub.2).sub.3      ##STR102##      NH NH 2HCl, 4 H.sub.2 O 274 80/20      26     ##STR103##      CH.sub.3      ##STR104##      H      ##STR105##      (CH.sub.2).sub.3      ##STR106##      NH NH      ##STR107##      245 40/60      27     ##STR108##      H      ##STR109##      H      ##STR110##      (CH.sub.2).sub.2      ##STR111##      NH NH Base, H.sub.2 O 150 15/85      28     ##STR112##      H      ##STR113##      H      ##STR114##      (CH.sub.2).sub.3 COOC.sub.2 H.sub.5 NH NH HCl, H.sub.2 O 228 50/50  29      ##STR115##      H      ##STR116##      H      ##STR117##      (CH.sub.2).sub.5 CONH.sub.2 NH NH HCl, 2 H.sub.2 O 256 65/35  30      ##STR118##      H      ##STR119##      H      ##STR120##      (CH.sub.2).sub.6 OH NH NH HCl, 4 H.sub.2 O 160 75/25               31      ##STR121##      H      ##STR122##      ##STR123##      ##STR124##      N(CH.sub.3).sub.2 NH NH 2HCl, 4 H.sub.2 O 275 50/50                32      ##STR125##      H      ##STR126##      H      ##STR127##      (CH.sub.2).sub.4 NHCOOC(CH.sub.3).sub.3 NH NH Base 165 50/50  33      ##STR128##      H      ##STR129##      H      ##STR130##      (CH.sub.2).sub.5 NHCOOC(CH.sub.3).sub.3 NH NH Base, 0,5 H.sub.2 O 180     55/45      34     ##STR131##      H      ##STR132##      H      ##STR133##      ##STR134##      NHCOOC(CH.sub.3).sub.3 NH NH HCl, 2 H.sub.2 O 200 40/60      35     ##STR135##      H      ##STR136##      H      ##STR137##      (CH.sub.2).sub.6 NHCOOC(CH.sub.3).sub.3 NH NH HCl, H.sub.2 O 204 50/50     36      ##STR138##      H      ##STR139##      H      ##STR140##      (CH.sub.2).sub.7 NHCOOC(CH.sub.3).sub.3 NH NH HCl, H.sub.2 O 205 50/50     37      ##STR141##      H      ##STR142##      H      ##STR143##      (CH.sub.2).sub.8 NHCOOC(CH.sub.3).sub.3 NH NH HCl, 1,5 H.sub.2 O 215     50/50      38     ##STR144##      H      ##STR145##      H      ##STR146##      (CH.sub.2).sub.4 NH.sub.2 NH NH 2HCl, 1,5 H.sub.2 O 230 50/50  39      ##STR147##      H      ##STR148##      H      ##STR149##      (CH.sub.2).sub.5 NH.sub.2 NH NH 2HCl, 2,5 H.sub.2 O 274 50/50  40      ##STR150##      H      ##STR151##      H      ##STR152##      (CH).sub.6 NH.sub.2 NH NH Base, 2/3 H.sub.2 O 170 50/50      41     ##STR153##      H      ##STR154##      H      ##STR155##      (CH.sub.2).sub.7 NH.sub.2 NH NH 2HCl, 4 H.sub.2 O 192 55/45  42      ##STR156##      H      ##STR157##      H      ##STR158##      (CH.sub.2).sub.8 NH.sub.2 NH NH 2HCl, 2 H.sub.2 O 228 60/40  43      ##STR159##      H      ##STR160##      H      ##STR161##      (CH).sub.9 NH.sub.2 NH NH      ##STR162##      238 50/50      44     ##STR163##      H      ##STR164##      H      ##STR165##      (CH.sub.2).sub.9 NH.sub.2 NH NH 2HCl, 2 H.sub.2 O 215 50/50  45      ##STR166##      H      ##STR167##      H      ##STR168##      (CH.sub.2).sub.7 NH.sub. 2 NH NH      ##STR169##      245 0/100.sup.(2) +38°6      46     ##STR170##      H      ##STR171##      H      ##STR172##      (CH.sub.2).sub.4      ##STR173##      NH NH 2HCl, 2 H.sub.2 O 185 50/50      47     ##STR174##      H      ##STR175##      H      ##STR176##      ##STR177##      NH.sub.2 NH NH      ##STR178##      207 0/100.sup.(2) +26°6      48     ##STR179##      H      ##STR180##      H      ##STR181##      ##STR182##      NH.sub.2 NH NH 2HCl, 2,5 H.sub.2 O 275 0/100.sup.(2) +23°   49      ##STR183##      H      ##STR184##      H      ##STR185##      ##STR186##      NH.sub.2 NH NH 2HCl, 3,5 H.sub.2 O 222 50/50      50     ##STR187##      H      ##STR188##      H      ##STR189##      ##STR190##      NH.sub.2 NH NH      ##STR191##      120 50/50      51     ##STR192##      H      ##STR193##      H      ##STR194##      (CH.sub.2).sub.5      ##STR195##      NH NH 2HCl, 4 H.sub.2 O 210 50/50      52     ##STR196##      H      ##STR197##      H      ##STR198##      (CH).sub.5      ##STR199##      NH NH      ##STR200##      245 50/50      53     ##STR201##      H      ##STR202##      H      ##STR203##      (CH.sub.2).sub.6      ##STR204##      NH NH      ##STR205##      218 50/50      54     ##STR206##      H      ##STR207##      H      ##STR208##      (CH.sub.2).sub.7      ##STR209##      NH NH 2HCl, 2 H.sub.2 O 240 55/45      55     ##STR210##      H      ##STR211##      H      ##STR212##      (CH.sub.2).sub.8      ##STR213##      NH NH      ##STR214##      205 55/45      56     ##STR215##      CH.sub.3      ##STR216##      H      ##STR217##      (CH.sub.2).sub.3 NCH.sub.3(CH.sub.2).sub.3 NH.sub.2 NH NH 3HCl, 5     H.sub.2 O 246 70/30      57     ##STR218##      H      ##STR219##      H      ##STR220##      ##STR221##      N(CH.sub.3).sub.2 NH NH 3 HCl, 4 H.sub.2 O 260 50/50      58     ##STR222##      H      ##STR223##      H      ##STR224##      ##STR225##      N(CH.sub.3).sub.2 NH NH 2 HCl, 3 H.sub.2      O 245 0/100.sup.(2) +16°1      59     ##STR226##      H      ##STR227##      H      ##STR228##      (CH.sub.2).sub.2      ##STR229##      NH NH HCl 228 50/50      60     ##STR230##      H      ##STR231##      H      ##STR232##      ##STR233##      N(CH.sub.3).sub.2 NH NH 2 HCl, 3 H.sub.2 O 220 100.sup.(4)      /0 -19°7      61     ##STR234##      H      ##STR235##      H      ##STR236##      ##STR237##      NH.sub.2 NH NH 2 HCl, 2,5 H.sub.2 O 222 0/100.sup.(2) +26°  62      ##STR238##      H      ##STR239##      H      ##STR240##      ##STR241##      N(CH.sub.3).sub.2 NH NH  208      63     ##STR242##      H      ##STR243##      H      ##STR244##      ##STR245##      N(CH.sub.3).sub.2 NH NH 3HCl, 3H.sub.2 O 185 100.sup.(4)      /0 +50°9      64     ##STR246##      H      ##STR247##      H      ##STR248##      ##STR249##      N(CH.sub.3).sub.2 NH NH      ##STR250##      186 50/50      65     ##STR251##      H      ##STR252##      H      ##STR253##      ##STR254##      N(CH.sub.3).sub.2 NH NH 2H.sub.2 O  40/60      66     ##STR255##      H      ##STR256##      CH.sub.3      ##STR257##      ##STR258##      N(CH.sub.3).sub.2 NH NH 2HCl, 2H.sub.2 O  60/40      67     ##STR259##      H      ##STR260##      H      ##STR261##      ##STR262##      N(CH.sub.3).sub.2 NH NH 2HCl, 4H.sub. 2 O  0/100.sup.(2) +52°     68      ##STR263##      H      ##STR264##      H      ##STR265##      ##STR266##      N(CH.sub.3).sub.2 NH NH 2HCl, 3H.sub.2     .sup.(1) c = 1, CH.sub.3 OH     .sup.(2) only one enantiomer in B     .sup.(3) cyclohexyl in the trans configuration     .sup.(4) only one enantiomer in A     .sup.(5) cyclohexyl in the cis configuration

We claim:
 1. A compound of the formula I ##STR267## in which Ar₁ isselected from the group consisting of naphthyl and phenyl, optionallysubstituted by a radical selected from the group consisting of Cl, F,(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, hydroxyle and (C₁ -C₄)dialkylamino, Ar₂is selected from the group consisting of phenyl and phenyl optionallysubstituted by Cl, F, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy and hydroxyle;R₁, R₂and R'₂ are selected independently of each other from the groupconsisting of H and (C₁ -C₄)alkyl, and optionally R₂ and R'₂ form adouble bond, or R₂ is attached to Ar₂ and represents a (C₁ -C₃)alkylene;R₃ and R₄ form, with the nitrogen atom to which they are attached, apyrrolidine; Z₁ represents (C₁ -C₁₂)alkylene, optionally interrupted orextended by a radical selected from the group consisting of (C₅-C₇)cycloalkyl and phenyl; Q₁ is selected from the group consisting ofmethyl, amino, (C₁ -C₄)alkoxycarbonylamino, (C₁ -C₄)alkylamino, di(C₁-C₄)-alkylamino, amidino, (C₁ -C₄)-alkylamidino, guanidino, (C₁-C₄)alkylguanidino, hydroxy, (C₁ -C₄)alkoxy, (C₂ -C₈)alkylcarbonyl,amino(C₁ -C₄)alkyl-N-(C₁ -C₄)alkylamino, carbamoyl, phenyl and phenylsubstituted by a radical selected from the group consisting of Cl, F,(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy and hydroxyle; Q₂ is selected from thegroup consisting of H and (C₁ -C₄)alkyl, Q₃ is selected from the groupconsisting of H and (C₁ -C₄)alkyl in the form of pure enantiomer ormixture thereof in any proportions as well as its salt with acid.
 2. Acompound according to claim 1 of formula I, in which Z₁ represents (C₄-C₉)alkylene and Q₁ contains a nitrogen atom attached to Z₁.
 3. Acompound according to claim 1, in which Q₁ represents an amino,guanidino, amidino, (C₁ -C₄)alkoxycarbonylamino, (C₁ -C₄)alkylamino,di(C₁ -C₄)alkylamino, guanidino, (C₁ -C₄)alkylguanidino, amino(C₁-C₄)alkyl-N-(C₁ -C₄)alkylamino group.
 4. A pharmaceutical compositioncomprising a therapeutically active amount of a compound of formula Iaccording to claim 1, in the form of pure enantiomers or a mixture ofenantiomers or one of their pharmaceutically acceptable salts combinedwith at least one excipient.
 5. A compound according to claim 1 offormula I in whichAr₁ is selected from the group consisting of naphthyl,phenyl and phenyl substituted by a radical selected from the groupconsisting of Cl, F, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy; Ar₂ is selected fromthe group consisting of phenyl and phenyl substituted by a radicalselected from the group consisting of Cl, F, (C₁ -C₃)alkyl and (C₁-C₃)alkoxy; R₁, R₂ and R'₂ are selected independently of each other fromthe group consisting of H and (C₁ -C₄)alkyl, and optionally R₂ and R'₂form a double bond, or R₂ is attached to Ar₂ and represents a (C₁-C₂)alkylene; R₃ and R₄ form, with the nitrogen atom to which they areattached, a pyrrolidine, Z₁ represents (C₁ -C₁₂)alkylene, optionallyinterrupted or extended by a radical selected from the group consistingof (C₅ -C₇)cycloalkyl and phenyl; Q₁ is selected from the groupconsisting of methyl, amino, (C₁ -C₄)alkoxycarbonylamino, (C₁-C₄)alkylamino, di(C₁ -C₄)-alkylamino, amidino, (C₁ -C₄)-alkylamidino,guanidino, (C₁ -C₄)alkylguanidino, hydroxy, (C₁ -C₄)alkoxy, (C₂-C₈)alkylcarbonyl, amino(C₁ -C₄)alkyl-N-(C₁ -C₄)alkylamino, carbamoyl,phenyl and phenyl substituted by a radical selected from the groupconsisting of Cl, F, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy; Q₂ is selected fromthe group consisting of H and (C₁ -C₄)alkyl; Q₃ is selected from thegroup consisting of H and (C₁ -C₄)-alkyl in the form of pure enantiomersor mixtures thereof in any proportions, as well as their salts withacids.